Throughout this specification, various publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference in this specification in order to more fully describe the state of the art to which this invention pertains.
Newborn infants with a variety of respiratory disorders are treated with positive pressure mechanical ventilation and oxygen therapy. This treatment is therapeutic, but can initiate a potent inflammatory response leading to acute lung injury and subsequent Bronchopulmonary Dysplasia or BPD. BPD begins as an acute lung injury that initiates a series of inflammatory responses which then evolve into chronic lung disease. The exact mechanisras responsible for pathophysiologic disruption to the lung in infants with BPD are not completely understood. One possibility is that oxidative insult caused by superoxide radicals is responsible for the initial, acute lung injury which ultimately leads to the development of BPD. If acute lung injury could be ameliorated, then it may be possible to prevent BPD.
Superoxide is a highly toxic free radical that may be an important component of pulmonary oxygen toxicity (1). SOD facilitates the conversion of superoxide radicals (O.sub.2.sup.-) to hydrogen peroxide (H.sub.2 O.sub.2). However, Crapo et al. found that free superoxide dismutase, administered by intraperitoneal injection or by aerosolization, failed to modify either the time course or the cumulative toxicity of 100% oxygen in adult rats (1).
Other experiments have been performed using free and liposome entrapped superoxide dismutase to determine the effect on pulmonary oxygen toxicity in rats (2,3). Seo et al. observed the effect of intratracheally administered free and liposome entrapped bovine superoxide dismutase and catalase by measuring the enzyme activity, oxygen radicals, pulmonary hemorrhage and survival rate after exposure to hyperoxia in adult rats (2). Free superoxide dismutase delivered to adult rats intratracheally with catalase had no protective effect against hyperoxia lung damage, while the intratracheally-administered liposome-entrapped superoxide dismutase and catalase enhanced the activity of total superoxide dismutase, Mn-superoxide dismutase and catalase in the rats (2) . PadrAanabhan et al. found that prior intratracheal adrainistration of liposome-encapsulated bovine CuZn-superoxide dismutase produced a significant increase in the activities of these enzymes in the lung tissue of rats exposed to hyperoxic levels of oxygen compared with that in control animals under the same conditions with free superoxide dismutase (3).
As demonstrated by the references discussed above (1-3), until now, attempts to protect animals from lethal effects of pure oxygen by intratracheal administration of free superoxide dismutase have been unsuccessful. The subject invention provides a method for intratracheally administering free human CuZn superoxide dismutase to protect humans from lung damage due to hyperoxia and hyperventilation.